Deriving benefit of early detection from biomarker-based prognostic models

Many prognostic models for cancer use biomarkers that have utility in early detection. For example, in prostate cancer, models predicting disease-specific survival use serum prostate-specific antigen levels. These models typically show that higher marker levels are associated with poorer prognosis. Consequently, they are often interpreted as indicating that detecting disease at a lower threshold of the biomarker is likely to generate a survival benefit. However, lowering the threshold of the biomarker is tantamount to early detection. For survival benefit to not be simply an artifact of starting the survival clock earlier, we must account for the lead time of early detection. It is not known whether the existing prognostic models imply a survival benefit under early detection once lead time has been accounted for. In this article, we investigate survival benefit implied by prognostic models where the predictor(s) of disease-specific survival are age and/or biomarker level at disease detection. We show that the benefit depends on the rate of biomarker change, the lead time, and the biomarker level at the original date of diagnosis as well as on the parameters of the prognostic model. Even if the prognostic model indicates that lowering the threshold of the biomarker is associated with longer disease-specific survival, this does not necessarily imply that early detection will confer an extension of life expectancy.